Novel 1,4-diarylpiperidine-4-methylureas as anti-hyperlipidemic agents: dual effectors on acyl-CoA:cholesterol O-acyltransferase and low-density lipoprotein receptor expression

Bioorg Med Chem Lett. 2009 Feb 15;19(4):1062-5. doi: 10.1016/j.bmcl.2009.01.020. Epub 2009 Jan 11.


A family of 1,4-diarylpiperidine-4-methylureas were designed and synthesized as novel dual effectors on ACAT and LDL receptor expression. We examined SAR of the synthesized compounds focusing on substitution at the three aromatic parts of the starting compound 1 and succeeded in identifying essential substituents for inhibition of ACAT and up-regulation of hepatic LDL receptor expression. Especially, we found that compound 12f, which can easily be prepared, has biological properties comparable to those of SMP-797, a promising ACAT inhibitor. In addition, the in vitro effects of 12f on lipid metabolism were substantially superior to those of a known ACAT inhibitor, Avasimibe.

MeSH terms

  • Combinatorial Chemistry Techniques
  • Humans
  • Methylurea Compounds / chemical synthesis*
  • Methylurea Compounds / chemistry
  • Methylurea Compounds / pharmacology*
  • Molecular Structure
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology*
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Receptors, LDL / drug effects*
  • Sterol O-Acyltransferase / antagonists & inhibitors
  • Sterol O-Acyltransferase / drug effects*
  • Structure-Activity Relationship


  • Methylurea Compounds
  • Naphthyridines
  • Piperidines
  • Receptors, LDL
  • SMP-797
  • Sterol O-Acyltransferase